We have demonstrated that acute and chronic administration of the postsynaptic aradrenergic receptor antagonist, prazosin, reduced ethanol drinking by selectively-bred alcohol-preferring (P) rats, a robust model for ethanol dependence. We have also demonstrated that prazosin treatment reduced operant ethanol selfadministration by outbred rats during ethanol withdrawal. In both experiments, prazosin administration did not decrease water consumption, demonstrating that the reduction of ethanol consumption was not due to performance deficits. These results are consistent with considerable evidence suggesting an important role for noradrenergic mechanisms in mediating ethanol dependence. Furthermore, recent results (presented in Exploratory Project 2) provide compelling evidence that prazosin administration likewise decreases relapse drinking in alcohol-dependent patients. Consequently, we now propose to further characterize the effect of prazosin administration on P rat ethanol consumption (Specific Aim 1) and to use this same P rat model to determine whether ethanol drinking is altered by administration of appropriate dosages of adrenergic receptor ligands which likewise decrease CMS noradrenergic signaling, but by different mechanisms (Specific Aim 2) - i.e., the post-synaptic p-adrenergic antagonist, propranolol, and the presynaptic a2-adrenergic agonist, clonidine. These studies will establish a well-characterized preclinical model for investigating changes in ethanol consumption in response to pharmacologic manipulations of noradrenergic regulation and begin to efficiently identify specific adrenergic receptor mechanisms, or combinations of mechanisms, likely to be most effectively targeted in human trials.